Dataset Information

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine.

ABSTRACT: BACKGROUND:Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. METHODS:Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate-mefloquine, chloroquine or artemether-lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7-9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. RESULTS:Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR?=?1.23, 0.88; 1.72, p?=?0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR?=?1.09, 1.03; 1.14, p?=?0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef - 0.02, - 0.005; - 0.03, p?=?0.01). All regimens were well tolerated. CONCLUSION:Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s ( http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/ ).

SUBMITTER: Daher A

PROVIDER: S-EPMC6757423 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine.

Daher André A Aljayyoussi Ghait G Pereira Dhelio D Lacerda Marcus V G MVG Alexandre Márcia A A MAA Nascimento Cristiana T CT Alves Júlio Castro JC da Fonseca Laís Bastos LB da Silva Diego Medeiros Dias DMD Pinto Douglas Pereira DP Rodrigues Danielle Fonseca DF Silvino Ana Carolina Rios ACR de Sousa Taís Nóbrega TN de Brito Cristiana Ferreira Alves CFA Ter Kuile Feiko O FO Lalloo David G DG

Malaria journal 20190923 1

<h4>Background</h4>Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has ...[more]

PMID: 31547827

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Project description:BackgroundVivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods.MethodsThree trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC-MS/MS method in accordance with current international regulatory requirements for bio-analytical methods.ResultsIn total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80-125% in all cases, the formulations tested were bioequivalent.ConclusionsIn conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

Project description:Background:In Nigeria, Artemisinin-based Combination Therapy (ACT) is the recommended first line antimalarial medicine for uncomplicated malaria. However, health care providers still continue the use of less efficacious medicines such as Sulphadoxine-pyrimethamine and chloroquine. We therefore determined preference for ACT (PFA) and factors associated with PFA among healthcare providers (HCP) in Lokoja, North-Central Nigeria as well as assessed healthcare providers' knowledge of malaria case management. Methods:We conducted a cross-sectional study among physicians, nurses, pharmacists, community health officers (CHOs), community health extension workers (CHEWs) and, patent and proprietary medicine vendors (PPMVs). Interviewer-administered questionnaires were administered to collect data on respondents' characteristics, previously received malaria case management training and knowledge of malaria treatment. Knowledge scores ≥3 were categorised as good, maximum obtainable being 5. Results:Of the 404 respondents, 214 (53.0%) were males. Overall, 219 (54.2%) respondents who received malaria case management training included PPMVs: 79 (65.8%), CHEWs: 25 (64.1%), CHOs: 5 (55.6%), nurses: 72 (48.7%), physicians: 35 (47.3%) and pharmacists: 3 (23.1%). Overall, 202 (50.0%) providers including physicians: 69 (93.2%), CHO: 8 (88.9%), CHEWs: 33 (84.6%), pharmacists: 8 (61.5%), nurses: 64 (43.2%) and PPMVs: 20 (16.5%), had good knowledge of malaria treatment guidelines. Overall, preference for ACT among healthcare providers was 39.6%. Physicians: 50 (67.6%), pharmacists: 7 (59.3%) CHOs: 5 (55.6%), CHEWS: 16 (41.0%), nurses: 56 (37.8%) and PPMV: 24 (19.8%) had PFA. Receiving malaria case management training (adjusted odds ratio [aOR]) = 2.3; CI = 1.4 - 3.7) and having good knowledge of malaria treatment (aOR = 4.0; CI = 2.4 - 6.7) were associated with PFA. Conclusions:Overall preference for ACT use was low among health care providers in this study. Preference for ACTs and proportion of health workers with good knowledge of malaria case management were even lower among PPMVs who had highest proportion of those who received malaria case management training. We recommend evaluation of current training quality, enhanced targeted training, follow-up supportive supervision of PPMVs and behavior change communication on ACT use.

Project description:BackgroundFollowing the development of resistance to anti-malarial mono-therapies, malaria endemic countries in Africa now use artemisinin-based combination therapy (ACT) as recommended first-line treatment for uncomplicated malaria. Patients' adherence to ACT is an important factor to ensure treatment efficacy, as well as to reduce the likelihood of parasite resistance to these drugs. This study reports adherence to a specific ACT, artemether-lumefantrine (AL), under conditions of routine clinical practice in Kenya.MethodThe study was undertaken in Garissa and Bunyala districts among outpatients of five government health facilities. Patients treated with AL were visited at home four days after having been prescribed the drug. Respondents (patients ≥ 15 years and caregivers of patients < 15 years) were interviewed using a standardized questionnaire, AL blister packs were physically inspected and the adherence status of patients was then recorded. Multivariate logistic regression modelling was used to determine predictors of adherence.ResultsOf the 918 patients included in the study, 588 (64.1%) were 'probably adherent', 291 (31.7%) were 'definitely non-adherent' and 39 (4.2%) were 'probably non-adherent'. Six factors were found to be significant predictors of adherence: patient knowledge of the ACT dosing regimen (odds ratio (OR) = 1.76; 95% CI = 1.32-2.35), patient age (OR = 1.65; 95% CI = 1.02-1.85), respondent age (OR = 1.37; 95% CI = 1.10-2.48), whether a respondent had seen AL before (OR = 1.46; 95% CI = 1.08-1.98), whether a patient had reported dislikes to AL (OR = 0.62 95% CI = 0.47-0.82) and whether a respondent had waited more than 24 hours to seek treatment (OR = 0.73; 95% CI = 0.54-0.99).ConclusionOverall, adherence to AL was found to be low in both Garissa and Bunyala districts, with patient knowledge of the AL dosing regimen found to be the strongest predictor of adherence. Interventions aimed at increasing community awareness of the AL dosing regimen, use of child friendly formulations and improving health workers' prescribing practices are likely to ensure higher adherence to AL and eventual treatment success.

Dataset Information

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine.

Publications

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine.

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